New avenues for anti-epileptic drug discovery and development.

Despite the introduction of over 15 third-generation anti-epileptic drugs, current medications fail to control seizures in 20-30% of patients. However, our understanding of the mechanisms mediating the development of epilepsy and the causes of drug resistance has grown substantially over the past decade, providing opportunities for the discovery and development of more efficacious anti-epileptic and anti-epileptogenic drugs. In this Review we discuss how previous preclinical models and clinical trial designs may have hampered the discovery of better treatments. We propose that future anti-epileptic drug development may be improved through a new joint endeavour between academia and the industry, through the identification and application of tools for new target-driven approaches, and through comparative preclinical proof-of-concept studies and innovative clinical trials designs.

Development of new treatment approaches for epilepsy: unmet needs and opportunities.

A working group was created to address clinical "gaps to care" as well as opportunities for development of new treatment approaches for epilepsy. The working group primarily comprised clinicians, trialists, and pharmacologists. The group identified a need for better animal models for both efficacy and tolerability, and noted that animal models for potential disease-modifying or antiepileptogenic effect should mirror conditions in human trials. For antiseizure drugs (ASDs), current animal models have not been validated with respect to their relationship to efficacy in common epilepsy syndromes. The group performed an "expert opinion" survey of perceived efficacy of the available ASDs, and identified a specific unmet need for ASDs to treat tonic-atonic and myoclonic seizures. No correlation has as yet been demonstrated between animal models of tolerability and adverse effects (AEs), versus tolerability in humans. There is a clear opportunity for improved therapies in relation to dose-related AEs. The group identified common and rare epilepsy syndromes that could represent opportunities for clinical trials. They identified opportunities for antiepileptogenic (AEG) therapies in both adults and children, acknowledging that the presence of a biomarker would substantially improve the chances of a successful trial. However, the group acknowledged that disease-modifying therapies (given after the first seizure or after the development of epilepsy) would be easier to study than AEG therapies.

Issues related to development of antiepileptogenic therapies.

Several preclinical proof-of-concept studies have provided evidence for positive treatment effects on epileptogenesis. However, none of these hypothetical treatments has advanced to the clinic. The experience in other fields of neurology such as stroke, Alzheimer's disease, or amyotrophic lateral sclerosis has indicated several problems in the design of preclinical studies, which likely contribute to failures in translating the positive preclinical data to the clinic. The Working Group on "Issues related to development of antiepileptogenic therapies" of the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES) has considered the possible problems that arise when moving from proof-of-concept antiepileptogenesis (AEG) studies to preclinical AEG trials, and eventually to clinical AEG trials. This article summarizes the discussions and provides recommendations on how to design a preclinical AEG monotherapy trial in adult animals. We specifically address study design, animal and model selection, number of studies needed, issues related to administration of the treatment, outcome measures, statistics, and reporting. In addition, we give recommendations for future actions to advance the preclinical AEG testing.

Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma.

Despite the development of various new antiepileptic drugs (AEDs) since the early 1990s, the available evidence indicates that the efficacy and tolerability of drug treatment of epilepsy has not substantially improved. What are the reasons for this apparent failure of modern AED development to discover drugs with higher efficacy? One reason is certainly the fact that, with few exceptions, all AEDs have been discovered by the same conventional animal models, particularly the maximal electroshock seizure test (MES) in rodents, which served as a critical gatekeeper. These tests have led to useful new AEDs, but obviously did not help developing AEDs with higher efficacy in as yet AED-resistant patients. This concern is not new but, surprisingly, has largely been unappreciated for several decades. A second-admittedly speculative-reason is that progress in pharmacologic treatment of drug-resistant epilepsy will not be made unless and until we develop drugs that specifically target the underlying disease. Although better preclinical approaches will not be able to circumvent regulatory requirements, more efficacious drugs may allow us to abandon clinically questionable trials with intentionally less efficacious controls and noninferiority designs, and require evidence for comparative effectiveness. The failure of AED development has led to increasing disappointment among clinicians, basic scientists, and industry and may halt any further improvement in the treatment of epilepsy unless we find ways out of this dilemma. Therefore, we need new concepts and fresh thinking about how to radically change and improve AED discovery and development. In this respect, the authors of this critical review will discuss several new ideas that may hopefully lead to more efficacious drug treatment of epilepsy in the future.

Prognosis of central retinal artery occlusion: local intraarterial fibrinolysis versus conservative treatment.

BACKGROUND AND PURPOSE: Local intraarterial fibrinolysis (LIF) is one of several methods used in treating central retinal artery occlusion (CRAO). We investigated whether LIF is more effective than conservative methods in the treatment of CRAO. METHODS: In this retrospective study, a total of 178 patients (125 men and 53 women) with CRAO were treated at the Eye Hospital of the University of Freiburg from 1980 to 2000. The average age of the patients was 66.8 years (SD, 12 years). In group I, 116 patients were treated conservatively by anterior chamber paracentesis, massage of the globe, isovolemic hemodilution, acetazolamide, Pentoxifyllin, acetylsalicylic acid, and reduction of arterial hypertension. Some combination but not all of the mentioned conservative methods were used in the conservatively treated patients. In group II, 62 patients receiving LIF received local injection of urokinase or recombinant tissue plasminogen activator into the proximal part of the ophthalmic artery. In case of ipsilateral carotid artery occlusion or high grade stenosis (14 of 62 patients), the thrombolytic agent was administered into the internal maxillary artery. RESULTS: Among 178 patients, the CRAO was subtotal in 130 (73.0%), incomplete in 39 (21.9%), and total in nine (5.1%). Statistical calculations showed a significantly better visual acuity in group II patients, who were treated with LIF, in comparison with group I patients, who were treated conservatively (P =.0022). CONCLUSION: For patients with CRAO, LIF is superior to conservative treatment.

New strategies for the identification of drugs to prevent the development or progression of epilepsy.

During the last decade, several new antiepileptic drugs (AEDs) have been introduced in Europe, the United States, or other parts of the world. Although the antiepileptic efficacy of these drugs is not superior to that of older AEDs, some of the new drugs offer advantages in terms of improved tolerability, ease of use, and reduced interaction potential with other drugs. However, the new AEDs have only a modest impact on patients with refractory epilepsies, so that about one third of patients with epilepsy continue to have seizures with current pharmacotherapies. Thus, there is a continuing need for new medical therapies in epilepsy. During the Workshop on "New Horizons in the Development of Antiepileptic Drugs" (November 28-29, 2001, Philadelphia, PA), one topic dealt with the critical re-evaluation of previous preclinical strategies for the discovery and the development of new AEDs. The discussion of this session, which was chaired by the authors, is summarized in this article. Main issues of the discussion were whether epilepsy is a progressive disease and whether refractory epilepsy is preventable, the use of acute versus chronic animal models in the discovery and development of new AEDs, models for drug-resistant epilepsy, mechanisms of drug resistance, alterations in adverse effect potential of AEDs by epilepsy, and advances in pharmacogenomics and our understanding of pharmacologic responsiveness in epilepsy. Overall, it was felt that the current preclinical strategies for the discovery and development of new AEDs have to be redefined in order to identify agents that are clearly superior to current medications.